[Not Applicable ]
Calcium channel blockers are a relatively recently discovered class of compounds which possess a wide spectrum of properties useful in the treatment of cardiovascular, cerebrovascular, intraocular, and other disorders. Calcium channel blockers were initially identified as a method for the control of hypertension (Fleckenstein et al. (1967) Z. Kreislaufforsch, 56: 716), and are routinely used in the control of hypertension and other disorders. In particular, calcium blockers have shown some useful therapeutic properties in the treatment of classic exertional angina, vasospastic angina, angina pectoris, acute myocardial infarction, cardiac arrhythmias, systemic arterial hypertension, pulmonary arterial hypertension, and cardiomyopathies. In addition, calcium channel blockers have shown therapeutic properties in the treatment of various cerebrovascular disorders, including but not limited to migraine headaches, and convulsive epilepsy.
Several structural classes of compounds are known which exhibit calcium channel blocking utility and have been used as therapeutics in a variety of contexts. The three major classes include dihydropynidines (e.g., nifedipine, felodipine, isradipine, and amlodipine), the benzothiazepines (e.g., diltiazem), and the phenylalkylamines (e.g., verapamil). Three calcium channel blockers are currently of primary clinical significance in the United States, verapamil, nifedipine and diltiazem. All three achieve their antihypertensive effect by inhibiting the entry of calcium ions into vascular smooth muscle. The ultimate effect is vasodilation. These calcium blockers are, however, contraindicated in various circumstances (e.g., where there is impaired left ventricular function). Thus, there is a need for other calcium blocking agents.
The present identifies previously unknown calcium channel blocking properties of retinoids, in particular retinol, and provides methods of treating pathological conditions characterized by and ameliorated by inhibition of cellular calcium influx using retinoids. Retinoids (e.g., vitamin A and analogues) are lipid-soluble and can therefore achieve extensive distribution within body tissues. They are also rapidly absorbed after oral or intravenous administration and, because of their affinity for fatty tissues, provide a reservoir that maintains elevated retinoid levels for some time after administration. In addition, the physiological tolerance for many retinoids (e.g., vitamin A) has been repeatedly demonstrated and well characterized.
Thus, in one embodiment, this invention provides a method of treating a disease in a mammal where the said disease is characterized by a symptom ameliorated by inhibition of cellular calcium influx. The method typically involves administering to the mammal an effective amount of a retinoid and a pharmacologically acceptable excipient. It will be appreciated that while a major application of the method involves treatment of humans, the methods are not so limited and treatment of virtually any mammal is contemplated. In a particularly preferred embodiment, the mammal is selected from the group of mammals having a disease characterized by one or more symptoms responsive to (ameliorated by) inhibition of calcium influx into a cell.
It is primarily contemplated that the methods will be practiced for the primary purpose of treatment of a condition one or more symptoms of which are responsive to calcium channel blockage. The methods do not contemplate administration of a retinoid for the purpose of diet supplementation. Thus, the retinoid is not a dietary supplement. The methods may thus additionally involve the step of assaying for retinoid-mediated amelioration of a symptom of a disease state. Typically the symptom will be one expected to be responsive to a calcium channel blocker. Similarly, the methods may additionally involve identifying a subject mammal (e.g., a patient) having a disease state expected to prove responsive to a calcium channel blocker.
The methods can be used to treat a wide variety of diseases including, but not limited to essential hypertension, hypertension associated with end stage renal failure, hypertension associated with pregnancy (preeclampsia), salt sensitivity hypertension, type II diabetes hypertension, hypertension associated with alcohol abuse, obesity associated hypertension, systolic hypertension in elderly, asthma, allergies, migraine headache, gastrointestinal motility disorders, Alzheimer""s disease, senile dementia, angina pectoris, premature labor, cerebrovascular diseases, and convulsive epilepsy. The methods, however, are particularly well suited for treatment of essential hypertension and intra-ocular hypertension.
Any of a variety of retinoids are suitable. Particularly preferred retinoids include retinoic acid and retinol, with retinol being most preferred. The pharmacologically acceptable excipient is preferably lipid compatible. A most preferred retinoid inhibits cellular influx of calcium through inhibition of voltage gated channels in particular L-type voltage-gated calcium channels.
In another embodiment, this invention provides a method of treating a disorder which is responsive to the partial or complete blockade of calcium channels of the central nervous system of a living mammal. Again the method involves administering to such a living mammal in need thereof, a therapeutically effective amount of a retinoid as described herein. The disorder can include stroke, anoxia, ischemia, migraine or epilepsy, psychosis, Parkinsonism, depression, or any other convulsive disorder. In still another embodiment, the method involves treating the degenerative changes, connected with stroke, anoxia, ischemia, migraine, Parkinsonism, epilepsy or any other convulsive disorder, responsive to the partial or complete blockade of calcium channels of the central nervous system of a living animal body, by administering to a living animal body in need thereof a therapeutically-effective amount of a retinoid as described herein.
In still another embodiment, this invention provides methods of inhibiting calcium influx into a mammalian cell. The methods involve contacting the cell with a retinoid. The retinoid is present in an amount sufficient to inhibit, partially or fully, a calcium channel, more preferably a L-type voltage-gated calcium channel. Virtually any retinoid is suitable, however in a preferred embodiment, the retinoid is retinol or retinoic acid, more preferably retinol. The cell can be virtually any mammalian cell, however preferred cells include muscle cells, more preferably smooth muscle cells, most preferably vascular muscle cells, or cells of the nervous system, more preferably cells of the central nervous system. The cell can be in vivo or in vitro.
In yet another embodiment this invention provides kits for the treatment of a disease in a mammal where the disease is characterized by a symptom ameliorated by inhibition of cellular calcium influx. The kits typically comprising a container containing a retinoid in a pharmaceutically acceptable excipient and instructional materials teaching the use of a retinoid to inhibit calcium influx in the treatment of a disease characterized by a symptom ameliorated by inhibition of cellular calcium influx. The disease includes, but is not limited to any essential hypertension, hypertension associated with end stage renal failure, hypertension associated with pregnancy (preeclampsia), salt sensitivity hypertension, type II diabetes hypertension, hypertension associated with alcohol abuse, obesity associated hypertension, systolic hypertension in elderly, asthma, allergies, migraine headache, gastrointestinal motility disorders, Alzheimer""s disease, senile dementia, angina pectoris, premature labor, cerebrovascular diseases, and convulsive epilepsy. Any of the retinoids described herein is suitable and a preferred retinoid is retinol.
The terms xe2x80x9ctreatingxe2x80x9d and xe2x80x9ctreatmentxe2x80x9d refer to any treatment of a disease in a mammal, particularly a human, and generally include: (i) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. Treating also refers to providing a beneficial alteration in one or more of the symptoms of a disease state or reducing or eliminating the disease state itself. It will be appreciated that a beneficial alteration can include transitory or permanent reduction or elimination of the symptom. It will also be appreciated that xe2x80x9ctreatingxe2x80x9d can also involve a reduction in actual adverse consequences or a reduction in the likelihood of adverse consequences of a pathological state. Thus treatment as used herein can also refer to prophylaxis. For example, treatment of hypertension can involve actual reduction or systolic or diastolic blood pressure. Alternatively treatment can reflect a reduction in the likelihood of stroke, e.g., where the reduction in likelihood is brought about by the reduction of blood pressure.
The term effective amount is intended to mean the amount of a drug, or multidrug therapeutic, which achieves a positive outcome on one or more symptoms of a disease state or which acts prophylactically to reduce the likelihood of one or more pathological symptoms or consequences of a disease state. Thus, for example, an effective amount of a drug for the treatment of hypertension can refer to an amount of a drug sufficient to transiently or permanently reduce blood pressure (e.g., diastolic pressure) or to reduce the likelihood of the onset of a stroke.
A calcium channel is a passive transport mechanism by which calcium ions move down their electrochemical gradient. In all cells, calcium concentration is low inside the cell (e.g., 10xe2x88x927 M) and high in the extracellular medium (e.g., 10xe2x88x923 M) and so a calcium channel allows calcium to go into the cell. By contrast, outward calcium transport takes place via xe2x80x9ca calcium pump,xe2x80x9d an entirely different mechanism which transports calcium against a concentration gradient (from the low concentration inside to the high concentration outside). An ion pump is therefore an active membrane structure, usually an enzyme (e.g., sodium ATPase) which requires energy (ATP: adenosine triphosphate) to carry ions across the membrane.
The term xe2x80x9cadministeringxe2x80x9d when used in the context of xe2x80x9cadministering to a mammalxe2x80x9d refers to delivering the drugs in question to a subject organism (e.g., mammal). Administration can be topical, intraperitoneal, subdermal, etc., as described herein.
The term xe2x80x9cpharmacologically acceptable excipientxe2x80x9d or xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d refers to a diluent or excipient suitable for administration to an organism. Administration can be topical or systemic, directed to particular tissues, organs or cells. The excipient is-essentially a carrier agent to facilitate administration of the active ingredient (e.g., retinoid). The excipient may contain auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, solubilizers, emulsifiers and the like.
The term dietary supplement is used to distinguish a compound taken to augment or replace an ingredient otherwise diminished or absent in a diet from a compound taken to specifically treat a particular disease/pathology. Thus, for example, a vitamin can be taken as a dietary supplement to ensure adequate dietary quantities of that vitamin or to supplement dietary defficiencies. Such a dietary supplement is, however, generally not taken to treat a specific disease or pathological state.
The term xe2x80x9ccontacting a cellxe2x80x9d when referring to contacting with a drug is used herein to refer to contacting in a manner such that the drug is internalized into the cell or into specific cellular components (e.g., plasma membrane). Where the drug is lipophilic or complexed with a lipid (e.g., a cationic lipid) simple contacting will result in transport (active and/or diffusive) into the cell. Alternatively the drug may itself be actively transported into the cell or may be administered with a carrier composition that is actively transported into the cell.
The terms xe2x80x9coptionalxe2x80x9d and xe2x80x9coptionallyxe2x80x9d mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, the phrase xe2x80x9coptional pharmaceutical excipientsxe2x80x9d indicates that a composition or dosage form so described may or may not include pharmaceutical excipients other than those specifically stated to be present, and that the formulation or dosage form so described includes instances in which optional excipients are present and instances in which they are not.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d refers to salts of the subject compounds which possess the desired pharmacological activity and which are neither biologically nor otherwise undesirable. Thus the retinoids of this invention may be administered in combination with pharmaceutically acceptable acid addition salts. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid and the like; or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like.
The terms xe2x80x9cfast releasexe2x80x9d and xe2x80x9cconventional releasexe2x80x9d refer to orally administered calcium channel blocker compositions that-are substantially completely dissolved and absorbed in the stomach or upper gastrointestinal tract.
The terms xe2x80x9clong actingxe2x80x9d and xe2x80x9csustained releasexe2x80x9d when used in reference to oral formulations, refer to calcium channel blocker compositions that are slowly and continuously dissolved and absorbed in the stomach and gastrointestinal tract over a period of at least two hours. Preferred long acting compositions and dosage forms exhibit plasma concentration profiles suitable for once daily administration of the dosage form.
The term xe2x80x9clipid compatiblexe2x80x9d when used with respect to a diluent or excipient indicates that the diluent or excipeint is capable of solubilizing, emulsifying, or suspending a lipophilic compound (e.g,. a retinoid).